Genes 2014, 5, 497-507; doi:10.3390/genes5030497 OPEN ACCESS
genes ISSN 2073-4425 www.mdpi.com/journal/genes Discussion
Lynch Syndrome: An Updated Review Rishabh Sehgal, Kieran Sheahan, Patrick R. O’Connell, Ann M. Hanly, Sean T. Martin and Desmond C. Winter * Centre for Colorectal Disease, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland; E-Mails:
[email protected] (R.S.);
[email protected] (K.S.);
[email protected] (R.O.C.);
[email protected] (A.M.H.);
[email protected] (S.T.M.) * Author to whom correspondence should be addressed; E-Mail:
[email protected]; Tel.: +353-1-2614-010; Fax: +353-1-2614-096. Received: 3 December 2013; in revised form: 30 April 2014 / Accepted: 9 May 2014 / Published: 27 June 2014
Abstract: Lynch syndrome is one of the most common cancer susceptibility syndromes. Individuals with Lynch syndrome have a 50%–70% lifetime risk of colorectal cancer, 40%–60% risk of endometrial cancer, and increased risks of several other malignancies. It is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. In a subset of patients, Lynch syndrome is caused by 3' end deletions of the EPCAM gene, which can lead to epigenetic silencing of the closely linked MSH2. Relying solely on age and family history based criteria inaccurately identifies eligibility for Lynch syndrome screening or testing in 25%–70% of cases. There has been a steady increase in Lynch syndrome tumor screening programs since 2000 and institutions are rapidly adopting a universal screening approach to identify the patients that would benefit from genetic counseling and germline testing. These include microsatellite instability testing and/or immunohistochemical testing to identify tumor mismatch repair deficiencies. However, universal screening is not standard across institutions. Furthermore, variation exists regarding the optimum method for tracking and disclosing results. In this review, we summarize traditional screening criteria for Lynch syndrome, and discuss universal screening methods. International guidelines are necessary to standardize Lynch syndrome high-risk clinics. Keywords: Lynch syndrome; genetics; screening; history; CRC clinic
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1. Introduction Approximately 2%–5% of all colorectal cancers (CRC) arise from a defined inherited cancer syndrome [1]. Lynch syndrome (formerly known as hereditary nonpolyposis colorectal cancer, HNPCC) and familial adenomatous polyposis (FAP) are autosomal dominant genetic disorders that comprise the majority of these. Other less common familial CRC syndromes include the hamartomatous syndromes, hyperplastic polyposis syndromes, the autosomal recessive MYH-associated polyposis syndrome, and familial juvenile polyposis. Although the global incidence of heritable CRC is relatively low when compared to their sporadic counterpart, early identification of such high-risk individuals and their families is important in order to commence timely screening and surveillance programs. Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Also genomic rearrangements within the epithelial cell adhesion molecule gene EPCAM can lead to silencing of the closely linked MSH2 gene in EPCAM-expressing tissues. CRCs in Lynch syndrome are characterized by an adenoma-carcinoma progression ratio of 1:1 (estimated adenoma-cancer transformation time 1–3 years), as compared to sporadic cases that have a ratio of 30:1 (estimated adenoma-cancer transformation time 8–17 years) [2]. If left untreated, the majority of polyps will become malignant as observed in approximately 70% of patients at age 70 and 80% of patients at 85 years. There is an increased incidence of metachronous and synchronous colon cancers with a second primary CRC developing in up to 30% after 10 years and 50% after 15 years [2]. Lynch syndrome predisposes to extracolonic malignancies involving the endometrium, stomach, ovaries, small bowel, hepatobiliary epithelium, uroepithelial epithelium and brain [1,2]. The aim of this manuscript is to review the history and genetics of Lynch syndrome and provide a discussion pertaining to the clinical and molecular diagnostics, universal tumor screening and changes in testing paradigms. 2. History of Lynch Syndrome The history of Lynch syndrome dates back to 1895 when Aldred Scott Warthin worked as the Chairman of the Department of Pathology at the University of Michigan, School of Medicine in Ann Arbor. He astutely observed his German seamstress to be depressed over the thought that she too would eventually succumb to gastric, colonic, or uterine cancer similar to the other members of her family. Indeed, she did die of endometrial cancer at an early age. Warthin studied her family in detail and published this large pedigree of 10 affected family members in 1913 outlining many generations affected by colonic, gastric and uterine cancers [3,4]. He performed an audit of 3600 cancer cases diagnosed in his laboratory between 1895 and 1912 and observed that approximately 15% of those had a positive family history of carcinoma. Warthin concluded that there was “some influence of heredity on cancer” [5]. An updated report on Family G was published in 1925. There was a higher familial preponderance for cancers of the gastrointestinal tract and uterus. Such cancers affected family members at a median age of 37.9 years and had a tendency for CRC to develop in the proximal colon. Warthin died in 1931 [5]. In 1966, Henry Lynch described two families from Nebraska (N) and Michigan (M) that had similar cancer patterns involving multi-generations that were akin to the original Family G. He studied the
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data from over 650 Family G members and later published his “Cancer Family ‘G’ Revisited” manuscript in 1971 [6] that solidified the evidence which characterized this syndromic disease as having an autosomal dominant inheritance pattern and an early age of onset (average age at onset
